Phosphorous trichloride, reaction products with 1,1'-biphenyl and 2,4-bis(1,1-dimethylethyl)phenol

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2015-04-19 - 2015-11-24

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Well-documented OECD GLP guideline study without deviations on the registered substance itself

Qualifier:

according to guideline

Guideline:

OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)

Version / remarks:

OECD Guideline No. 421 for testing of chemicals, “Reproduction/ Developmental Toxicity Screening Test” adopted on 27th July 1995.

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

National Good Laboratory Practice Compliance Monitoring Authority, Government of India, Department of science and Technology, Technology Bhawan, New Mehrauli Road, New Delhi-110016, India

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Department of Safety Assessment, Advinus Therapeutics Limited, Bengaluru 560 058, India
- Age at study initiation: (P) 11-12 wks
- Weight at study initiation: (P) Males: 299.00 ± 28.24 g (G1), 288.90 ± 16.20 g (G2), 287.91 ± 17.05 g (G3), 282.69 ± 17.81 g (G4); Females: 207.45 ± 13.24 g (G1), 207.06 ± 11.97 g (G2), 206.58 ± 10.12 g (G3), 206.38 ± 11.61 g (G4); At the commencement of the treatment, the weight variation of animals used did not exceed ± 20 % of the mean body weight in each sex and group.
- Fasting period before study: not applicable, feeding study
- Housing: Rats were housed under standard laboratory conditions, air conditioned with adequate fresh air supply.
Pre mating: Two rats of same sex were housed per cage in sterilized standard polysulfone cages (Size: approximately L 425 x B 266 x H 185 mm), with stainless steel top grill having facilities for holding powder food in hopper and drinking water in polycarbonate bottles.
Mating: During mating, two rats (one male and one female) were housed in standard polysulfone cages with stainless steel top grill having facilities for holding powder food in hopper and drinking water in polycarbonate bottles.
Post-mating: After confirming presence of sperm in the vaginal smear or vaginal plugs (Day 0 of pregnancy), the mated pairs were separated. Males were housed with their former cage mates while females were housed individually in polysulfone cages. The sterilised nesting material (paper shreds) was provided near-term.
Bedding was steam sterilized clean corn cob and changed along with the cage at least once a week.
- Diet (e.g. ad libitum): Teklad Certified (2014C) Global 14 % Protein Rodent Maintenance Diet - powder (Certified) manufactured by Harlan Laboratories B.V. Maasheseweg 87c PO Box 553, 5800, AN Venray, The Netherlands, was provided ad libitum to the rats.
- Water (e.g. ad libitum): Deep bore-well water passed through activated charcoal filter and exposed to UV rays in ‘Aquaguard’ on-line water filter-cum-purifier manufactured by Eureka Forbes Ltd., Mumbai 400 001, India, was provided ad libitum to animals in polycarbonate bottles with stainless steel sipper tubes.
- Acclimation period: five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-24 °C
- Humidity (%): 60 – 68%,
- Air changes (per hr): 12-15
- Photoperiod (hrs dark / hrs light): 12 hours light and 12 hours dark cycle

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on exposure:

DIET PREPARATION

Test Diet Preparation
Following procedure was followed when 6 kg of experimental diet was prepared.
The quantities of test item (G2: 15 g, G3: 30 g and G4: 60 g) was weighed in the labeled glass beaker and mixed with approximately 0.5 kg of basal diet in a mixer grinder for two minutes to prepare premix. This premix was mixed with approximately 0.5 kg of diet for low, mid and high dose groups in stainless steel drum (approximately 2 minutes) and then added in portions to the remaining bulk diet (approximately 5.0 kg) and mixed in stainless steel ribbon blender for 20 minutes. For animals in control group (G1), 6.0 kg of the basal diet was mixed in stainless steel ribbon blender for 20 minutes.
Following procedure was followed when the quantity is less than 4 kg. For example 2 kg of experimental diet was prepared.
The quantities of test item (G2: 5 g, G3: 10 g and G4: 20 g) was weighed in the labeled glass beaker and mixed with approximately 0.3 kg of basal diet in a mixer grinder for two minutes to prepare premix. This premix was mixed with remaining bulk diet (approximately 1.7 kg) for low, mid and high dose groups in stainless steel drum and mixed thoroughly using a spoon for 5 minutes. For animals in control group (G1), 2.0 kg of the basal diet was mixed in stainless steel drum thoroughly using a spoon for 5 minutes.
The quantity of experimental diet prepared, the amount of test item weighed was varied depending on the requirement. The details were recorded in the raw data. The formulated diet was prepared as and when required, however, the frequency of mixing was within the stability period.
The left over formulated diet was sent for incineration.

Storage of Experimental Fortified Diet
The experimental fortified diet was not stored in the experimental room and it was prepared as and when required.
The prepared fortified diet was collected in the polyethylene bags within labelled stainless steel drums and used immediately after the preparation on the same day.

Details on mating procedure:

- M/F ratio per cage: 1:1
- Length of cohabitation: Cohabitation was continued until evidence of sperms in the vaginal smear and /or vaginal plug.
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged (how): mated females were housed individually until lactation day 4

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Stability and Homogeneity and Concentration of the Test Item in the Diet
Stability and homogeneity of test item in diet was determined at nominal concentrations of 2500 and 10000 ppm under Advinus Study No.G10101 and found to be stable up to 7 days when stored at room temperature.

Homogeneity and Active Ingredient (AI) Analysis of Test Item in the Experimental Fortified Diet
The homogeneity and active ingredient (a.i) analysis was carried out on Day 1 and during week 4 of the treatment period. Six samples were taken (2 each from top, middle and bottom layers) of the fortified diet of each group to determine the homogeneity and active ingredient of the test item in the experimental fortified food.
For the Control group, one composite sample was collected in labelled plastic containers as scheduled above.
All the collected samples were sent to Analytical R&D Department of Advinus Therapeutics Limited, Bengaluru at ambient conditions for analysis. Samples were analyzed for the test item content using the method validated under Advinus study No.: G10101. Fortified food was considered acceptable, as the mean results were within ± 20% of the claimed concentration.

Duration of treatment / exposure:

Males: The test item fortified diet was fed ad libitum daily to specific group of rats for 2 weeks prior to mating and the treatment was continued during the mating period and until the last female parturition.
Females: The test item fortified diet was fed ad libitum daily to specific group of rats for 2 weeks prior to the mating period and was continued through mating, pregnancy and up to lactation day 4. Pups were sacrificed on lactation day 4 along with females (dams).
Rats in control group were fed basal diet.

Frequency of treatment:

continuously

Remarks:

Doses / Concentrations:
2500, 5000 and 10000 ppm
Basis:
nominal in diet

No. of animals per sex per dose:

10 / sex / dose

Control animals:

yes, plain diet

Details on study design:

- Dose selection rationale: based on results of 28-day oral gavage study

Positive control:

not required

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All rats were observed once daily for appearance, behaviour and clinical/toxic signs. All animals were observed for morbidity and mortality twice daily. As there were no clinical signs, the observation was carried out once during holidays.
Dams and offsprings were observed for physical and gross behavioural abnormalities.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: see above

BODY WEIGHT: Yes
- Time schedule for examinations: Individual body weights were recorded at the beginning (on day 1) of the treatment and at weekly thereafter and at termination.
All dams were weighed on Gestation Days (GD) 0, 7, 14 and 20 and on Lactation Days 0 and 4 and weights were recorded.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
Cagewise food consumption was calculated by using the food consumed at weekly interval per cage and dividing by the number of rats per cage and the number of days in the intervening period to determine the food intake/rat/day.
Food consumption was not measured during the cohabitation period.
Food consumption of pregnant dams of the treated groups was recorded on GD 0-7, 7-14 and 14-20 and for Day 0-4 of lactation period.

Oestrous cyclicity (parental animals):

not determined

Sperm parameters (parental animals):

Parameters examined in P male parental generations:
testis weight, epididymis weight, Histopathological examination of the testes included qualitative assessment of stages of spermatogenesis

Litter observations:

STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: not required

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical abnormalities

GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: All surviving animals until the last female parturition
- Maternal animals: All surviving animals on lactation day 4

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.

HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated below were prepared for microscopic examination and weighed, respectively.

Postmortem examinations (offspring):

SACRIFICE
- All the F1 offspring 4 days of age.
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as below:

GROSS NECROPSY
- All the sacrificed pups were examined for malformations and subjected to gross pathological examination.

Statistics:

The statistical analysis of the experimental data was carried out using the validated package in Excel and also using licensed copies of SYSTAT Statistical package ver.12.0. All quantitative variables like body weight, food consumption, net food intake, organ weights and organ weight ratios, pup No., pup weight, precoital interval, gestation length, litter size were tested for normality (Shapiro-Wilk test) and homogeneity of variances (Levene’s test) within the group before performing a one-factor ANOVA modeling by treatment groups. Non-optimal (non-normal or heteroscedastic) data were transformed, before using ANOVA. Dunnett’s pair-wise comparison of the treated means with the control mean was done for the significant group differences.
Pre-implantation loss (%), post implantation loss (%), no. of corpora lutea, implantations, pre-coital interval and gestation length (days) were analysed after suitable transformation (√ x + ½) of the data. One-way analysis of variance (ANOVA) was carried out for the transformed data.
Z test was performed for testing the differences in proportions for mating and fertility indices.
Mean Implantation index, live birth index and day 4 survival index were performed by Kruskal-Wallis Test.
All analyses and comparisons were evaluated at the 5% (P≤0.05) level. Statistically significant differences (P≤0.05), indicated by the aforementioned tests was designated by the superscripts throughout the report as stated below:
+/-: Significantly higher (+)/lower (-) than the control group.

Reproductive indices:

Male mating index
Male fertility index
Female mating index
Fecundity index
Female fertility index
Mean number of corpora lutea (CL)/group
Mean number of implantations/group
Implantation index
Percentage of pre-implantation loss per group
Percentage of Post implantation loss
Gestation index

Offspring viability indices:

Mean litter size per group
Live birth index
Day 4 survival index

Clinical signs:

no effects observed

Description (incidence and severity):

No mortality or clinical signs were observed at any of the doses tested.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Food consumption and body weight change was not affected in any treated group when compared to the control group. Significant decrease in the food consumption was observed in females during week 1 at 10000 ppm dose, but considered incidental.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

Food consumption and body weight change was not affected in any treated group when compared to the control group. Significant decrease in the food consumption was observed in females during week 1 at 10000 ppm dose, but considered incidental.

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

Microscopic examination revealed no toxicologically relevant test item-related changes in the reproductive organs of males and females.

Other effects:

no effects observed

Description (incidence and severity):

Test substance intake: The mean daily food intake and test item intake (g/kg Bwt/day) at 2500, 5000 and 10000 ppm did not statistically differ from control.

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

Description (incidence and severity):

There were no treatment-related effects on the mean precoital interval and gestation length and fertility indices between controls and treated groups.

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
No mortality or clinical signs were observed at any of the doses tested.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
Males: Mean body weights were not affected in any treated group when compared to the control group.
Females: Prior to the cohabitation period, mean body weights were not affected in any treated group when compared to the control group.

Food consumption was not affected in any treated group when compared to the control group. However, significant decrease in the food consumption was observed in females during week 1 at 10000 ppm dose. This decrease in the food consumption was considered incidental as there was no associated change in the body weight.

Maternal Body Weights and Food Consumption during the Gestation Period: No significant changes in maternal body weights were observed during different intervals of gestation period at any of the doses tested, when compared with control.
The significantly higher food consumption observed at 10000 ppm during gestation days 0-7, 7-14 and 0-20 when compared to control group and considered incidental as there were no associated significant changes in the body weights observed.

Maternal Body Weights and Food Consumption during the Lactation Period: No significant changes in the maternal body weights were observed during different intervals of lactation period, when compared with control.
The significantly higher food consumption was observed at 10000 ppm during lactation days 0-4 when compared to control group and considered incidental as there were no associated significant changes in the body weights were observed.

TEST SUBSTANCE INTAKE (PARENTAL ANIMALS)
The mean daily food intake and test item intake (g/kg Bwt/day) at 2500, 5000 and 10000 ppm did not statistically differ from control.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
Fertility Index: There were no treatment-related effects on the mean precoital interval and gestation length and fertility indices between controls and treated groups.
Uterine/Implantation Data: No treatment-related effects were observed with respect to number of implantations, and percentage of pre and post implantation losses when compared to control means.

ORGAN WEIGHTS (PARENTAL ANIMALS)
No relevant test item-related changes were observed with respect to terminal body weights, organ weights and organ to body weight ratios when compared with control means. There were no test item-related changes in terminal body weights in both sexes of all groups compared to the control group. Testes/epididymidal weights/ratios were not affected by the test item administration.

GROSS PATHOLOGY (PARENTAL ANIMALS)
Gross examination of the adult rats sacrificed on lactation Day 4 did not reveal toxicologically relevant lesions in any dose group.

HISTOPATHOLOGY (PARENTAL ANIMALS)
Microscopic examination revealed no toxicologically relevant test item-related changes in the reproductive organs of males and females.
Solitary incidence of minimal degeneration of seminiferous tubules in the testes and cell debris in the epididymides observed in a male rat (Rr3887) at 10000 ppm was considered as spontaneous change.
All other microscopic findings observed in the treatment group including control group were considered as spontaneous findings normally found in this strain and species at this age.

Dose descriptor:

NOAEL

Effect level:

607.85 mg/kg bw/day

Based on:

test mat.

Sex:

male

Basis for effect level:

other: see 'Remark'

Dose descriptor:

NOAEL

Effect level:

783.98 mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

other: see 'Remark'

Clinical signs:

not examined

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Histopathological findings:

not examined

VIABILITY (OFFSPRING)
No statistically significant changes in mean litter size were observed. Live pups showed no external abnormalities in any of the treated group when compared to the control group.
No statistically significant changes in the live birth index and day 4 survival index at in any of the treated groups when compared to control group.
The Mean total number of pups on Lactation Days 0 and 4 per litter was not affected in any of the treated group when compared to the control group.
Mean number of male pups on Lactation Days 0 and 4 were not affected in any of the treated group when compared to the control group.
Significant increase in the mean number of female pups per litter on Lactation Days 0 and 4 was observed at 10000 ppm and was considered incidental, as there is no change in the mean total number of pups per litter on Lactation Days 0 and 4.

BODY WEIGHT (OFFSPRING)
The mean body weight of male and female and total number of pups per litter were unaffected by the treatment at all the doses tested, when compared to control group.

GROSS PATHOLOGY (OFFSPRING)
Gross examination of the pups sacrificed on lactation Day 4 did not reveal toxicologically relevant lesions in any dose group.

Remarks on result:

not determinable due to absence of adverse toxic effects

Reproductive effects observed:

not specified

Due to space limitations, tables are attached

Conclusions:

The study was conducted under GLP according to OECD guideline 421 on the registered substance itself. The method is to be considered scientifically reasonable with no deficiencies in documentation or any deviations, the validity criteria are fulfilled. Hence, the results can be considered as reliable to assess the potential of the test item to be a reproductive toxicant (screening).
The oral dietary administration of the test item to male and female Wistar rats produced no clinical signs or mortality. There were no toxicologically significant effects on body weights in males and food consumption in males and females and in body weights and body weight gains in females during the treatment period. No toxicologically significant changes were observed in pre-coital time, gestation length, mating and fertility parameters. No treatment-related effects were observed in the number of implantations, percentage of post implantation losses, mean litter size and mean viable litter size. There were no external abnormalities in live pups. There were no treatment related gross and microscopic changes in reproductive organ of parents. The testes and epididymides weights were not affected by the treatment with the test item.
The No Observed Adverse Effect Level (NOAEL) of the test item is considered to be 10000 ppm which is equivalent to 607.85 mg/kg Bwt/day for males and 793.98 mg/kg Bwt/day for females after daily oral dietary administration to male and female Wistar rats for a period covering pre-mating, mating and post-mating, i.e. about 7 weeks in males and about 8 weeks in females.
Hence, no classification as reproductive toxicant is triggered.

Executive summary:

The objective of this OECD 421 GLP study was to generate information concerning the effects of the test item on male and female reproductive performance in Wistar rats such as gonadal function, mating behaviour, conception, development of the conceptus and parturition.

 

Methods:

The test item admixed feed was provided at the doses of 2500, 5000 and 10000 ppm to male and female Wistar rats. Similarly, the basal diet was administered to rats in the control groups. Each group consisted of 10 male and 10 female rats.

The stability and homogeneity of test item in diet was determined at nominal concentrations of 2500 and 10000 ppm and found to be stable up to 7 days when stored at room temperature.

The test item admixed feed was analyzed for homogeneity and active ingredient (a.i) concentration on Day 1 and during week 4 of the treatment period. The results indicated that the analyzed concentrations were found to be homogeneous and mean results were within the ± 20 % of the claimed concentration.

Males were fed with test item fortified diet for a minimum period of seven weeks, up to and until the last female parturition. This included a minimum of two weeks prior to mating, during the mating period and three weeks post mating. Each male was observed for mortality and morbidity twice daily. Body weight was recorded at the beginning of the treatment, weekly thereafter and at termination. Food consumption was recorded weekly except during the cohabitation period where in food consumption was not measured. After the last female parturition completion, all male rats were sacrificed, a gross necropsy was performed, and testes and epididymides were weighed.

Females were fed with test item fortified diet for two weeks prior to mating, the variable time to conception, the duration of pregnancy and four days after delivery, up to and including the day before scheduled sacrifice. Each female was observed for mortality and morbidity twice daily. Body weight was recorded at the beginning of the treatment, weekly prior to mating, on Gestation Days 0, 7, 14 and 20 and on Lactation Days 0 and 4. Food consumption was recorded on Gestation Days 7, 14 and 20 and on Lactation Day 4. The number, weight, survival and mortality of pups were observed during the lactation period. Female rats and all surviving pups were sacrificed on Lactation Day 4 and a gross necropsy was performed.

Tissues collected from all animals (testes, epididymides, prostate and seminal vesicles for males; ovaries for females) in the control and high dose groups were examined microscopically for histopathological changes (with special emphasis on stages of spermatogenesis in male gonads and histopathological examination.).

 

Results:

The oral administration of the test item admixed feed at dose levels of 2500, 5000 and 10000 ppm to male (two weeks prior to mating, during the mating period and three weeks post mating) and female Wistar rats (two weeks prior to mating, during time to conception, during pregnancy and four days after delivery, up to the day before scheduled sacrifice) was well tolerated. No test item-related mortality or clinical signs occurred. Body weight, food consumption, pre-coital time, gestation length, mating and fertility parameters, number of implantations, percentage of pre- and post implantation losses, mean litter size and mean viable litter size as well as testes and epididymides weights were not affected by treatment. External evaluation of pups as well as gross and microscopic examination of the reproductive organs of the parent animals revealed no adverse test item-related changes.

 

Conclusion:

Daily oral dietary administration of the test item to male and female Wistar rats at dose levels of 2500, 5000 and 10000 ppm for at least 2 weeks prior to mating, during mating, and 3 weeks post mating (males) or at least 2 weeks prior to mating, during mating, and during pregnancy until 4 days after delivery (females) did not induce any relevant adverse effects. The No Observed Adverse Effect Level (NOAEL) of the test item is considered to be 10000 ppm which is equivalent to 607.85 mg/kg Bwt/day for males and 793.98 mg/kg Bwt/day for females.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

793.98 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Well-documented and -performed OECD 421 GLP guideline study on the registered substance itself assessed with Klimisch 1, which is required according to REACH Annex VIII. No implausibilities were seen, all tested dose levels did not result in any adverse effects, including the highest dose tested, 10000 ppm in feed over / (males) or 8 (females) weeks. Hence, no data gaps nor the need for further testing was identified, the results are plausible, the tonnage-driven data requirements under REACH are fully met. So, the database is of high quality.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

There is a well-documented and -performed OECD 421 GLP guideline study on the registered substance itself available, assessed with Klimisch 1, which is required according to REACH Annex VIII. This study is suitable for a screening of the potential reproductive / developmental toxicity effects of the registered substance, as the substance was administered during all periods relevant for reproductive performance and development, i.e. dosing pre-, during and post-mating. Consistently, all tested dose levels did not result in any adverse effects, including the highest dose tested, 10000 ppm in feed. Taking into account the determined feed intake, this value can be re-calculated to mg/kg units, which so corresponds to 607.85 mg/kg Bwt/day for males and 793.98 mg/kg Bwt/day for females. Since both levels did not result in any adverse effects, the actual NOAEL could hence be much higher, and pregnant females are in general more sensitive than males, the higher value, i.e. 793.98 mg/kg Bwt/day, can be used for further risk assessment, any uncertainties will be sufficiently covered by the assessment (uncertainty) factors employed during risk assessment.

There is no indication given that the results are not suitable and transferrable to humans, no data gaps were identified as the information requirements for REACH Annex VIII are fully met and consistent results are available. So, this endpoint is sufficiently covered and the substance does not need to be classified as reproductive or developmental toxicant.

Short description of key information:
Toxicity to reproduction: 7 (males) / 8 (females) week reproductive toxicity screening study oral (feed), rat (Wistar rats-HsdHanTM: WIST), m/f, dosing pre-, during and post-mating, 2500, 5000 and 10000 ppm in diet (OECD 421, GLP): No adverse effects observed, NOAEL = 10000 ppm in feed (corresponds to 607.85 mg/kg Bwt/day for males and 793.98 mg/kg Bwt/day for females)

Justification for selection of Effect on fertility via oral route:
only study available

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Although there is no study available for this endpoint exclusively, the given results available from the above mentioned OECD 421 Reproduction/ Developmental Toxicity Screening Test clearly indicate that the substance is not a developmental toxicant, as no effects or gross abnormalities were seen in any of the offsprings including the highest dosage group. According to REACH Annex VIII, this information totally covers the present data requirements.

Justification for classification or non-classification

In the available OECD 421 study, the oral dietary administration of the test item to male and female Wistar rats produced no clinical signs or mortality. There were no toxicologically significant effects on body weights in males and food consumption in males and females and in body weights and body weight gains in females during the treatment period. No toxicologically significant changes were observed in pre-coital time, gestation length, mating and fertility parameters. No treatment-related effects were observed in the number of implantations, percentage of post implantation losses, mean litter size and mean viable litter size. There were no external abnormalities in live pups. There were no treatment related gross and microscopic changes in reproductive organ of parents. The testes and epididymides weights were not affected by the treatment with the test item. No effects were seen incuding at the highest dose tested, 10000 ppm in feed (corresponding to 607.85 mg/kg Bwt/day for males and 793.98 mg/kg Bwt/day for females). Hence, there is no effect seen which could trigger the classification as reproductive or developmental toxicant according to Regulation 1272/2008.